Systems for peripheral nerve stimulation

ABSTRACT

A peripheral nerve stimulator can be used to stimulate a peripheral nerve to treat essential tremor, Parkinsonian tremor, and other forms of tremor. The stimulator can have electrodes that are placed circumferentially around the patient&#39;s wrist or arm. Specific nerves in the wrist or arm can be targeted by appropriate spacing of the electrodes, Positioning the electrodes on generally opposing sides of the target nerve can result in improved stimulation of the nerve. The stimulation pattern may alternate between the nerves. Improved stimulation algorithms can incorporate tremor feedback, external data, predictive adaptation, and long-term monitoring data.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/247,310 filed on Jan. 14, 2019, now issued as U.S. Pat. No.10,561,839, which is in turn a continuation of U.S. patent applicationSer. No. 15/721,475 filed on Sep. 29, 2017, now issued as U.S. Pat. No.10,179,238, which is in turn a continuation of U.S. patent applicationSer. No. 15/354,943 filed on Nov. 17, 2016, now issued as U.S. Pat. No.9,802,041, which is in turn a continuation of International PatentApplication No. PCT/US2015/033809, filed Jun. 2, 2015, titled “SYSTEMSAND METHODS FOR PERIPHERAL NERVE STIMULATION TO TREAT TREMOR,” nowInternational Publication No. WO 2015/187712, which claims priority toU.S. Provisional Application No. 62/006,565, filed Jun. 2, 2014, U.S.Provisional Application No. 62/006,555, filed Jun. 2, 2014, U.S.Provisional Application No. 62/083,424, filed Nov. 24, 2014, and U.S.Provisional Application No. 62/157,116, filed May 5, 2015, each of theforegoing of which is herein incorporated by reference in its entirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

FIELD

Embodiments of the invention relate generally to systems, devices, andmethods for treating tremor, and more specifically relate to system,devices, and methods for treating tremor by stimulation of peripheralnerve(s).

BACKGROUND

Hand tremors are one of the most common movement disorders, affecting anestimated 10 million people in the U.S., with growing numbers due to theaging population. The prevalence increases with age, increasing from5-10% of the population over 65, to above 20% over 95. Essential tremoris characterized by oscillatory movement, for example between 4-12 Hz,affecting distal limbs, like the hands. Unlike Parkinson's tremor, whichexists at rest, essential tremor affects postural and kineticactivities, meaning tremor is invoked by holding a limb against gravityor during intentional movement, respectively. Tremor is also asignificant problem for patients with other diseases, such asorthostatic tremor, multiple sclerosis and Parkinson's Disease.Treatment options for these conditions are limited, have undesirableside effects, or have high risk relative to the potential benefits, soalternative treatment, is warranted. A number of conditions, such astremors, can be treated through some form of transcutancous peripheralnerve stimulation.

Designing a device to accomplish such a treatment is challenging. Onedifficulty in designing a product for patients with tremors is creatingu device that is easy to position and configure for individuals whosehands are unsteady. People have a wide variation in wrist diameters,nerve locations, nerve depolarization characteristics, and skinconduction that leads to challenges in designing a device tocomfortably, safely, and reliably target peripheral nerves forstimulation across a broad population. For instance, in a wrist-worndevice targeting the median, ulnar, and radial nerves at the wrist, theband circumference for tire adult population would have to vary from13.5-19.8 cm to accommodate 5th percentile female to 95th percentilemale. See Henry Dreyfus Associates, “The Measure of Man and Woman”,Wiley, 2001. In addition to differences in size, there are variations inthe location, depth, and branching of nerves. Thus, a system and methodthat can reliably stimulate one or more nerves in the wrist across awide range of wrist sizes would be advantageous in treating handtremors.

A second challenge to designing such a device is that tremors varybetween different people. Even within the same person tremor can occurat variable times throughout the day, depending on multiple factors,including but not limited to the patient's stress level, fatigue, and\diet. Thus, individually customized and responsive therapy capable oftreating the tremor when it occurs or is likely to occur can provide amore effective, yet power efficient device.

SUMMARY OF THE DISCLOSURE

The present invention relates generally to systems, devices, and methodsfor treating tremor, and more specifically relate to system, devices,and methods for treating tremor by stimulation of peripheral nerve(s).It should be understood that some of the features described inconnection with one embodiment may be combined with another embodiment.

In some embodiments, a system for treating a patient suffering fromtremor is provided. The system can include a pulse generator; and acircumferential band adapted to be secured to the patient's arm orwrist, the band supporting a first and a second electrode in electricalcommunication with the pulse generator, the first and second electrodesbeing spaced on the band so as to deliver electrical stimuli from thepulse generator to the patient to preferentially excite a first nerveselected from the patient's median, radial or ulnar nerve, the first andsecond electrodes being arranged and configured such that in atransverse cross-sectional plane of the arm or wrist there is a 90degree to 180 degree angle between a line connecting the first nerve andthe first electrode and a line connecting the first nerve and the secondelectrode.

In some embodiments, the band supports a third electrode in electricalcommunication, with the pulse generator, the first and third electrodesbeing spaced on the band so as to deliver electrical stimuli from thepulse generator to the patient to preferentially excite a second nerveselected from the patient's median, radial or ulnar nerve, the first andthird electrodes being arranged and configured such that in a transversecross-sectional plane of the arm or wrist there is a 90 degree to 80degree angle between a line connecting the second nerve and the firstelectrode and a line connecting the second nerve and the thirdelectrode, where the first nerve and the second nerve are differentnerves.

In some embodiments, when the circumferential band is secured around thepatient's arm or wrist, the first electrode is positioned on a dorsalside of the patient's arm or wrist, the second electrode is positionedon the ventral side of the patient's arm or wrist, and the thirdelectrode is positioned on the patient's arm or wrist in between thefirst electrode and second electrode.

In some embodiments, the electrodes each have a center and the electrodecenters are spaced about 5 mm to one quarter the circumference of thewrist or arm apart.

In some embodiments, the band comprises flexible circuitry, and the bandis fastened to the housing through a riveted connector that alsoprovides electrical communication between the flexible circuitry of theband and the pulse generator.

In some embodiments, the housing has a distal end configured to beoriented towards the patient's hand, and a proximal end configured to beoriented away from the patient's hand, such that the band, the firstelectrode, and the second electrode are closer to the distal end of thehousing than to the proximal end of the housing.

In some embodiments, the pulse generator is the only pulse generator,and the system further includes a switch matrix configured to switch thepulse generator between at least one pair of electrodes.

In some embodiments, the switch matrix comprises a single high voltagesource and ground.

In some embodiments, each electrode in the switch matrix is associatedwith its own set of protection circuitry.

In some embodiments, the system further includes a controller configuredto deliver an alternating stimulation pattern from the pulse generatorto the electrodes.

In some embodiments, the stimulation pattern includes an application ofa plurality of alternating bursts of electrical stimulation delivered ina first pulse train to a first nerve selected from the patient's median,radial or ulnar nerve, and a second pulse train delivered to a differentnerve selected from the patient's median, radial or ulnar nerve, whereinthe first pulse train and the second pulse train are offset by about onehalf the tremor period.

In some embodiments, the stimulation pattern includes an application ofa plurality of bursts of electrical stimulation, such that each burstincludes a stimulation frequency between about 50 Hz and 2,000 Hz, and apulse width between about 50 microsecond and 1 millisecond, and a pulseshape selected from the group consisting of monophasic rectangular,biphasic asymmetric rectangular, or biphasic symmetric rectangular.

In some embodiments, the stimulation pattern includes an application ofa plurality of alternating bursts of electrical stimulation, such thateach burst comprises a duration of about one half the tremor period.

In some embodiments, the system further includes a motion sensorconfigured to measure motion of the patient's arm or wrist.

In some embodiments, the motion sensor includes a 3-axis gyroscope oraccelerometer.

In some embodiments, the system further includes a controller incommunication with the pulse generator and the motion sensor, thecontroller programmed to determine one or more characteristics of thetremor based on a signal generated by the motion sensor.

In some embodiments, the one or more characteristics of the tremor isselected from the group consisting of the tremor frequency, the tremoramplitude, and the tremor phase.

In some embodiments, the controller is further programmed to adjust oneor more parameters of the electrical stimuli based on the determinedcharacteristics of the tremor.

In some embodiments, the first electrode, second electrode, and thirdelectrode are fabricated on n disposable and replaceable flexiblesubstrate with one or more electrical connectors for electricalcommunication with the pulse generator.

In some embodiments, each electrode further includes a pull tab to aidin fastening and removal.

In some embodiments, the housing and/or bands comprise a plurality ofelectrical snaps for removably receiving the first electrode, secondelectrode, and third electrode.

In some embodiments, the first electrode, second electrode, and thirdelectrode are disposed on a thin liner with a spacing that correspondsto the position of the plurality of electrical snaps on the housingand/or band.

In some embodiments, the system further includes an adhesive disposed onthe thin liner around the electrodes.

In some embodiments, the system further includes a cradle that securelysupports the housing and the bands such that the first electrode, secondelectrode, and third electrode can be attached to the housing and/orhand.

In some embodiments, the cradle has a cavity for securely receiving thehousing such that the base of the housing is exposed.

In some embodiments, the first electrode, second electrode, and thirdelectrode are recessed into the housing or band such that the electrodesextend a predetermined distance from the housing or band.

In some embodiments, the first electrode and second electrode aredisposable and replaceable.

In some embodiments, the hand includes moldable indentations configuredto encompass the electrodes and protect them from dehydration.

In some embodiments, the first electrode and the second electrode arecoated with an electrically conductive hydrogel.

In some embodiments, the first electrode and the second electrode areconnected with a foam backing layer.

In some embodiments, the foam backing layer includes a serpentine shapedportion between the electrodes.

In some embodiments, the housing includes one or more depressible userinput buttons, each button located on a side of the housing, and a broadbracing surface on the opposite side of the housing from each button.

In some embodiments, the housing has a skin contact side with a curvedsurface that follows the curvature of the patient's arm or wrist.

In some embodiments, the system further includes a rechargeable batteryand an inductive coil configured to receive power from art externalsource to inductively charge the battery. The rechargeable battery andinductive coil can be enclosed in the housing.

In some embodiments, the electrodes have a diameter or width betweenabout 5 mm and one-quarter the circumference of the arm or wrist.

In some embodiments, the system has only three electrodes, in otherembodiments, the system only has two electrodes.

In some embodiments, the polarity of the electrodes connected to thestimulator is switchable.

In some embodiments, a method of treating a patient suffering fromtremor is provided. The method can include placing a band comprising afirst electrode and a second electrode around the patient's arm or wristin a configuration such that in the transverse cross-sectional plane ofthe arm or wrist there is a 90 degree to 180 degree angle between a lineextending between a first nerve and the first electrode and a lineextending between the first nerve and the second electrode, the firstnerve selected from the patient's median, radial and ulnar nerves,wherein the first and second electrodes are spaced a predetermineddistance apart; and delivering a first electrical stimulus from theelectrodes to excite the first nerve to reduce the patient's tremor.

In some embodiments, the band includes a third electrode spaced apredetermined distance apart from the first and second electrodes suchthat there is a 90 degree to 180 degree angle between a line extendingbetween a second nerve and the first electrode and a line extendingbetween the second nerve and the third electrode, the second nerveselected from the patient's median, radial and ulnar nerves.

In some embodiments, the method further includes delivering a secondelectrical stimulus from the first electrode and the third electrode toexcite the second nerve.

In some embodiments, first nerve is the median nerve and the secondnerve is the radial nerve.

In some embodiments, the band is operatively connected to a housingenclosing a motion sensor, and the method further includes measuring oneor more characteristics of the tremor with the motion sensor while thepatient performs a tremor-invoking task.

In some embodiments, the tremor-invoking task is an instructed task or akinetic activity.

In some embodiments, the instructed task is a postural hold and thekinetic activity is drawing or writing.

In some embodiments, the tremor-invoking task is a task the patientperforms uninstructed as part of normal daily activities.

In some embodiments, the measured characteristics of the tremor includea frequency spectrum of the tremor.

In some embodiments, the method further includes determining a tremorfrequency by determining a center frequency peak within a 4 to 12 Hzrange in the frequency spectrum of the tremor.

In some embodiments, the measured characteristics of the tremor includean amplitude of the tremor.

In some embodiments, the method further includes temporally offsettingthe first electrical stimulus from the second electrical stimulus by aperiod of time based on a period of the tremor.

In some embodiments, the period of time is a function of the period ofthe tremor divided by the number of nerves that are stimulated.

In some embodiments, the number of nerves that are stimulated is two.

In some embodiments, the first electrode is in electrical communicationto a first contact of a stimulator and the second electrode is inelectrical communication to a second contact of the stimulator, thestimulator configured to generate an electrical pulse between of thefirst electrode and the second electrode, the electrical pulse having apolarity.

In some embodiments, the method further comprises switching the firstcontact and the second contact of the stimulator such that the firstelectrode is in electrical communication with the second contact and thesecond electrode is in electrical communication with the first contactin order to change the polarity of the electrical pulse so that thefirst electrical stimulus is biphasic.

In some embodiments, the method further includes measuring motion of thepatient; determining the energy, amplitude, frequency, and pattern ofthe measured motion; and separating non-tremor motion from tremor motionbased in part on the determined energy, amplitude, frequency, andpattern of the measured motion.

In some embodiments, the method further includes determining astimulation sensation threshold and a muscle contraction or discomfortthreshold.

In some embodiments, the method further includes increasing an amplitudeof the first electrical stimulus from the stimulation sensationthreshold towards the muscle contraction or discomfort threshold.

In some embodiments, the step of increasing the amplitude of the firstelectrical stimulus includes increasing the amplitude linearly orexponentially.

In some embodiments, the step of increasing the amplitude of the firstelectrical stimulus includes increasing the amplitude in a series ofprogressively greater peak amplitudes separated by reductions inamplitude.

In some embodiments, the step of increasing the amplitude of the firstelectrical stimulus includes increasing the amplitude to a value greaterthan the muscle contraction or discomfort threshold and then reducingthe amplitude to below the muscle contraction or discomfort threshold.

In some embodiments, the step of increasing the amplitude of the firstelectrical stimulus includes increasing the amplitude in a series ofstepwise increments, where each increment in amplitude is held for apredetermined duration.

In some embodiments, each stepwise increment in amplitude is followed bya decrease in amplitude that is smaller in magnitude than the increasein each stepwise increment.

In some embodiments, the first electrical stimulus and the secondelectrical stimulus are delivered out of phase to the tremor.

In some embodiments, the method further includes determining the tremorfrequency and phase by analyzing a signal from a motion sensor worn bythe patient selected from the group consisting of an accelerometer, agyroscope, a magnetometer, and a bend sensor.

In some embodiments, the step of using motion sensors to measurecharacteristics of the tremor during a tremor-invoking task and usingthese tremor characteristics to determine parameters of the stimulationwaveform is done in real-time.

In some embodiments, the first electrical stimulus and/or the secondelectrical stimulus have a stochastic resonance electrical stimulationpattern.

In some embodiments, the method further includes determining anelectrical stimulation level that is above a sensation threshold andbelow a muscle contraction threshold and the patient's pain tolerancethreshold.

In some embodiments, the positioning of the band is verified byparesthesia in the patient's hand.

In some embodiments, the positioning of the band is based in part on acomparison of a shape of the housing with one or more anatomicalfeatures.

In some embodiments, the first electrical stimulus has a durationbetween about 20 and 60 minutes.

In some embodiments, the method further includes measuring motion of thepatient's arm or wrist during a specific task; and determiningcharacteristics of the tremor from the measured motion.

In some embodiments, the specific task is a postural, kinetic, orintentional movement.

In some embodiments, the characteristics of the tremor include tremorfrequency; and the method further includes alternating a timing of burstpatterns of the first electrical stimulus based on the tremor frequency.

In some embodiments, a method of treating a patient suffering fromtremor is provided. The method can include determining a circumferenceof a patient's wrist; providing a band and housing having apredetermined circumferential spacing for a first electrode, a secondelectrode, and a third electrode, where the predeterminedcircumferential spacing is based on the determined circumference of thepatient's wrist, where the housing encloses a pulse generator configuredto be in electrical communication with the first electrode, the secondelectrode, and the third electrode, where the band and housing areconfigured to be positioned on the wrist such that the first electrodeis positioned approximately along the midline of the dorsal side of thearm or wrist, the second electrode is positioned approximately along themidline of the ventral side of the arm or wrist, and the third electrodeis positioned in between the first electrode and second electrode, wherethe first electrode and the second electrode form a first electrode pairand the first electrode and third electrode form a second electrodepair; stimulating a first nerve by delivering a first electricalstimulus between the first electrode pair; and stimulating a secondnerve by delivering a second electrical stimulus between the secondelectrode pair.

In some embodiments, a method of treating a patient suffering fromtremor is provided. The method can include determining a circumferenceof a patient's wrist; selecting a band and housing having apredetermined circumferential spacing for a first electrode, a secondelectrode, and a third electrode, where the predeterminedcircumferential spacing is based on the determined circumference of thepatient's wrist, where the housing encloses a pulse generator configuredto be in electrical communication with the first electrode, the secondelectrode, and the third electrode; positioning the band and housing onthe wrist such that the first electrode is positioned approximatelyalong the midline of the dorsal side of the arm or wrist, the secondelectrode is positioned approximately along the midline of the ventralside arm or wrist, and the third electrode is positioned in between thefirst electrode and second electrode, where the first electrode and thesecond electrode form a first electrode pair and the first electrode andthird electrode form a second electrode pair; stimulating a first nerveby delivering a first electrical stimulus between the first electrodepair; and stimulating a second nerve by delivering a second electricalstimulus between the second electrode pair.

In some embodiments, one or more electrodes can be connected to a givenstimulator lead at the same time.

In some embodiments, a device is provided. The device can include anadjustable array of electrodes configured to be adjustable to target oneor more nerves of the subject; a skin interface in contact with theadjustable array of electrodes; an adjustable band in contact with theadjustable array of electrodes; and an electronics box in contact withthe band.

In some embodiments, the electrodes are a linear array.

In some embodiments, the electrodes circumvent a limb of the subject.

In some embodiments, the limb is a wrist.

In some embodiments, electrodes on the dorsal side of the limb is thecommon electrode.

In some embodiments, electrodes on the ventral side of the limb aresignal electrodes.

In some embodiments, the nerve is a nerve selected from the groupconsisting of: ulnar, median, and radial, or any combination thereof.

In some embodiments, the electronics is configured to switch currentbetween electrodes in the array of electrodes.

In some embodiments, at least two electrodes in the array of electrodesare the same size.

In some embodiments, at least two electrodes in the array of electrodesare different sizes.

In some embodiments, the array of electrodes configured for the dorsalside of a limb are different sizes than the electrodes of the arrayconfigured for the ventral side of the limb.

In some embodiments, electrodes in the array of electrodes areconfigured to accept a maximum amount of current.

In some embodiments, an impedance value between two or more electrodesin the array of electrodes is from 20 nF to 120 nF.

In some embodiments, an impedance value between two or more electrodesin the array of electrodes is from 5 nF to 300 nF.

In some embodiments, the array of electrodes includes a materialselected from the group consisting of AglAgCl, Ag, Au, Stainless steel,and conductive rubber.

In some embodiments, the skin interface includes a material selectedfrom the group consisting of: a hydrogel, a conductive fluid, aconductive gel, a conductive lotion, a fabric, or any combinationthereof.

In some embodiments, the skin interface includes a hydrogel.

In some embodiments, the hydrogel has an impedance value that preventscurrent leakage between electrodes.

In some embodiments, an impedance value of the two or more electrodes isdependent on the spacing of the electrodes.

In some embodiments, the skin interface layer has ranges from above 1000ohm-cm to 100 kohm-cm in volume resistivity

In some embodiments, the device has some current leakage between anelectrode in the array of electrodes and the skin interface.

In some embodiments, the leakage current is less than 50%.

In some embodiments, the leakage current is less than 30%.

In some embodiments, the leakage current is less than 10%.

In some embodiments, a method for fitting a subject with a tremor with aneuromodulation device is provided. The method can include contacting alimb of the subject with a device comprising an adjustable array ofelectrodes, configured to be adjustable to one or more nerves of thesubject; determining a location of nerve response, and fitting thesubject with the device based on the location of nerve response.

In some embodiments, the nerve response is paresthesia.

In some embodiments, the method of determining the nerve responseincludes stimulating electrodes in the array of electrodes.

In some embodiments, the location of nerve response is indicative ofnerve activation.

In some embodiments, the method of determining nerve response includescontacting a different portion of the limb with a feedback device.

In some embodiments, the limb includes a wrist, and the differentportion comprises a finger.

In some embodiments, the feedback device includes a measurementelectrode.

In some embodiments, activation of the electrode indicates which nervehas been excited.

In some embodiments, the method of determining nerve response includesidentifying positional movement of the limb.

In some embodiments, the fitting includes placing the device on the limbfor activating a nerve in the limb with the device.

In some embodiments, the fitting includes selecting electrodes foractivation that are necessary for the activation. In some embodiments,parameters can be stored in memory and referenced by the microcontrollerin the device during treatment.

In some embodiments, the activating includes peripheral nervestimulation.

In some embodiments, the activating treats a tremor in the subject.

Although many of the embodiments have been described having two or threeelectrodes, ii should be understood that other embodiments may haveadditional electrodes, particularly if additional nerves are beingtarget.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe claims that follow. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIGS. 1A-1E illustrate various view's of an embodiment of a device andsystem that provides peripheral nerve stimulation, targeting individualnerves, to reduce tremor. FIG. 1E shows a schematic of a housing of thedevice that contains various components.

FIG. 2A illustrates a graph showing a reduction in tremor for a patientwith a customized stimulation from an embodiment of the array concept.FIG. 2B demonstrates the improvement in a spiral drawn by a patientbefore stimulation (at left) and after stimulation (at right).

FIGS. 3A-3C illustrate various embodiments of electrodes on a wrist,including a common electrode on the back of the wrist to reduce thenumber of electrodes needed to stimulate multiple nerves and electrodespositioned on the circumference of the wrist to selectively stimulatethe nerves targeted for excitation.

FIGS. 4A and 4B illustrate how in some embodiments the band width canvary depending on how the electrodes are arranged. FIG. 4A illustratesthat in line placement increases the size of the wrist banded needed.FIG. 4B illustrates that if the electrodes are placed along thecircumference with a common electrode, the band width decreases.

FIGS. 5A-5C illustrate various embodiments of different fixed spacingsbetween the electrode pads that were able to successfully targetpredetermined nerves in patients with varying anatomy.

FIG. 6 illustrates a diagram showing how the maximum size of theelectrodes can be calculated in some embodiments.

FIGS. 7A and 7B illustrate how the electrode connector can be moved outof the band and into the box to simplify the band.

FIGS. 8A and 8B illustrate an embodiment of conventional median nerveexcitation with electrodes longitudinally placed along the nerve (FIG.8B) versus excitation by an array of electrodes circumferentiallydistributed around the wrist (FIG. 8A).

FIG. 9 illustrates an embodiment of a flexible circuit stimulationarray. The substrate is flexible and able to wrap and conform around thewrist.

FIG. 10 illustrates an embodiment of a flexible circuit fabricated withsmaller rectangular pads but similar inter-element spacing as comparedto FIG. 9 to reduce the effective area of stimulation and increase thesensitivity of the array to target a specific nerve.

FIG. 11 illustrates an embodiment of a a flexible circuit fabricatedwith a circular electrode array.

FIG. 12 illustrates an embodiment of a switching circuit that allows asingle stimulator to address each electrode individually.

FIG. 13 illustrates and embodiment of a uni-directional conductivemicroarray of conductive elements in an electrically insulating carrier.

FIGS. 14A-14D illustrate the effect on current density when an electrodepeels from the skin for a conventional electrode and array.

FIGS. 15A-15D illustrates the effect of an electrical short on currentdensity for a conventional electrode and an array.

FIG. 16 illustrates an embodiment of a potential construction for anelectrode array.

FIG. 17 illustrates a typical patterned waveform between median andradial nerve used to treat essential tremor.

FIG. 18 illustrates a patterned waveform with N different nerves. Theduration of each burst is equal to the period of tremor divided by N.Each nerve is excited by a burst and the whole pattern repeats in a timeequal to the tremor period.

FIG. 19 illustrates an embodiment where the order of the pulse trains ondifferent nerves are randomized.

FIG. 20 illustrates a patterned waveform showing pauses in thestimulation.

FIG. 21 illustrates how a switch matrix can be used to produce abiphasic waveform.

FIG. 22 illustrates how measurements of nerve conduction can be used toautomatically determine which electrodes stimulate a target nerve.

FIGS. 23A and 23B illustrate how changing the electrode selection orposition affects the electric current field shape and density in thewrist.

FIGS. 24A-24F illustrate how various characteristics of the tremor canbe used as feedback to adapt stimulation delivered to the patient. Inaddition, predictive adaptation based on information gathered from thepatient's calendar, for example, can be used to trigger stimulation.

FIG. 25A-25C illustrate how big data compiled from large populationscombined can improve disease and tremor classification, which allowsrecommendations of treatments as well as long-term monitoring of tremor.

FIG. 26 illustrates a flow chart that shows how tremor feedback,long-term monitoring data, external data, and predictive adaptation canbe used to adjust treatment.

FIGS. 27A and 27B present results from two subjects that show therelationship between patient sensation and stimulation amplitude.

FIGS. 28A-28D illustrate various ramp types.

FIGS. 29A and 29B illustrate a series of small ramps that increasestimulation level, with either pauses or a small decrease in levelbetween each ramp.

FIG. 30 is a flow chart of how tremor frequency can be calculated from3-axis sensors.

FIGS. 31A and 31B illustrate how a false or inaccurate peak in tremorfrequency can be detected.

FIG. 32 illustrates how the tremor frequency varies over the course of aday.

FIG. 33 illustrates how other physical activities could be mistaken fortremor.

FIG. 34 illustrates a regression model of tremor versus non-tremoractivities as an example of how to identify activities from which tocalculate the center frequency of tremor.

FIG. 35 illustrates a cross-sectional view of electrode snaps recessedinto compressed neoprene to create a comfortable seal between the bandand skin.

FIGS. 36A-36C illustrate various views of an adjustable buckle incombination with a snap or button fastener, which allows the wearer toadjust the tension of the armband after it has been fastened and securedto their arm/wrist.

FIGS. 37A and 37B illustrate an embodiment of an electrode with anon-sticky pull tab.

FIG. 38 illustrates electrodes that are appropriately spaced on a thinfilm liner for easier installation into the device.

FIGS. 39A-39C illustrate electrodes connected by a single foam backing,including a concept for a serpentine connection.

FIGS. 40A and 40B illustrate an embodiment of a cradle used to supportthe device when installing and removing the electrodes.

FIG. 41 illustrates an embodiment of the wearable stimulator where theelectrodes are shifted distally with respect to the electronics housingto more easily target nerves distally on the wrist.

FIGS. 42A-42D illustrate various ways of locating buttons on the housingopposite a bracing surface.

FIG. 43 illustrates one embodiment of an electrode with round snaps.

FIGS. 44A-44C illustrate an embodiment of a band that can be fastened tothe user's wrist or arm using only a single hand.

FIGS. 45A and 45B illustrate an embodiment of a band and itselectronics.

FIG. 46 illustrates an embodiment of a charging block with a keyed shapethat can help in alignment and plugging of the device into a basestation.

FIGS. 47A-47C illustrate another embodiment of a band and an inductivecharger.

FIGS. 48A-48C illustrate an embodiment of a one-fingered glove withfasteners and electrodes.

DETAILED DESCRIPTION

One aspect of this invention is a device and system that providesperipheral nerve stimulation, targeting individual nerves (FIGA-1E). Oneaspect of this invention is a device and system 10 that allowscustomization and optimization of transcutaneous electrical treatment toan individual. In particular, the device 10 described is for electricalstimulation of the median, radial, or ulnar nerves in the wrist fortreating tremors. Targeting those specific nerves and utilizingappropriately customized stimulation results in more effective therapy(e.g., reduced tremor).

FIGS. 1A-1E illustrate an embodiment of a device and system 10 thatprovides peripheral nerve stimulation, targeting individual nerves, toreduce tremor. In some embodiments, the device 10 is designed to be wornon the wrist or arm. In some embodiments, electronics located in awatch-like housing 12 measure tremor and also generate an electricalstimulation waveform, electrical contacts in a band 14 and/or housing 12transmit the stimulation waveform to the disposable electrodes 16. Thelocation of the contacts in the band 12 is arranged such that specificnerves are targeted at the wrist, such as the median and radial nerves.The electronics housing 12 also can have a digital display screen toprovide feedback about the stimulation and measured tremorcharacteristics and history to the wearer of the device.

In some embodiments, the treatment device 10 is a wrist worn deviceconsisting of 1) an array of electrodes 16 encircling the wrist, 2) askit) interlace to ensure good electrical contact to the person, 3) anelectronics box or housing 12 containing the stimulator or pulsegenerator 18, sensors 20, and other associated electronics such as acontroller or processor 22 for executing instructions, memory 24 forstoring instructions, a user interface 26 which can include a displayand buttons, a communications module 28, a battery 30 that can berechargeable, and optionally an inductive coil 32 for charging thebattery 30, and the like, and 4) a band to hold all the componentstogether and securely fasten the device around the wrist of anindividual.

This system has shown dramatic tremor reduction after providingelectrical stimulation to nerves in the patient's wrist in accordancesto the embodiments described herein. FIG. 2A is an example of the tremorreduction detected using a gyroscope to measure the tremor energy duringa postural hold. FIG. 2B is an example of tire tremor reduction detectedby having the patient draw a spiral.

Circumferential, Spaced Electrodes

One aspect of our device is the use of only three electrodes to targettwo nerves (e.g., median and radial), with a shared or common electrode300 placed on the dorsal side of the wrist (FIG. 3A). In someembodiments, the common electrode 300 can be placed approximately on thelongitudinal midline of the dorsal side of the arm or wrist. In someembodiments, an additional electrode 302 can be placed approximately onthe longitudinal midline of the ventral side of the arm or wrist totarget the median nerve. In some embodiments, yet another electrode 304can be placed in between the common electrode 300 and the ventrallyplaced electrode 302 to target the radial nerve. In some embodiments,yet another electrode can be placed to target the ulnar nerve. Moregenerally, combining subsets of electrodes permits targeting N nerveswith fewer than N electrodes.

FIGS. 3B and 3C illustrate the positions of the common electrode 300,the ventrally placed electrode 302, and the radial electrode 304 inrelation to the median nerve 306 and the radial nerve 308 in atransverse cross-sectional plane of the patient's wrist or arm. Theelectrodes 300, 302, 304 are positioned such that in a projection intothe transverse cross-sectional plane of the arm or wrist there is a 90degree to 180 degree angle, α1, between a line connecting the mediannerve 306 and the center of the common electrode 300 and a lineconnecting the median nerve 306 and the center of the ventrally placedelectrode 302, and there is a 90 degree to 180 degree angle, α2, betweena line connecting the radial nerve 308 and the common electrode 300 anda line connecting the radial nerve 308 and the radial electrode 304. Theangles α1 and α2 may each be in either a counter-clockwise direction (asα1 is shown in FIG. 3B) or in a clockwise direction (as α1 is shown inFIG. 3C). More generally, electrodes can be spaced apart by apredetermined distance such that when the electrodes are positionedcircumferentially around a patient's wrist, one of the angles formedbetween each electrode pair and its target nerve is between about 90degrees and 180 degrees. Such an orientation results in each electrodeof the electrode pair being placed generally on opposite sides of thetarget nerve. In other words, the target nerve is positionedapproximately between the electrode pair.

As shown in FIGS. 4A and 4B, three electrodes 400, 402, 404 placedcircumferentially around the wrist allow: (1) a reduced band widthcompared to a typical arrangement where the two electrodes 400′, 402′are longitudinally placed along the same nerve, and (2) targeting deeperinto the tissue by having the pair of electrodes across from each otherto target each nerve. Although the embodiments have been described withreference to three electrodes for the stimulation of two nerves, it isunderstood that alternative embodiments can utilize two electrodes tostimulate a single nerve, where the two electrodes can have a fixedspacing to allow the electrodes to stimulate the nerve from opposingsides of the nerve. Similarly, other embodiments can utilize more thanthree electrodes. For instance, an additional electrode can be added totarget the ulnar nerve. In addition, different combination of electrodescan be used to target one or more nerves from the group of the median,radial, and ulnar nerves.

Mapping the nerves of a number of individuals with different wrist sizesby selectively stimulating circumferential locations on the wrist andverifying where the user feels paresthesia in order to identify themedian, radial, and ulnar nerve showed the variability in nerve locationrelative to wrist size, as well as the high individual variable inphysiology. Individual nerves can be targeted with electrodes positionedat the correct location, such as the positions shown in FIG. 3A or anarray allowing selection of those individual nerves, as discussed below.

Table 1 presents data showing individuals' wrist sizes and thestimulation locations needed to excite the radial, median, and ulnarnerve. Notice that multiple locations can sometimes target the samenerve and also that individuals of the same wrist circumference andwidth can often have very different responses. Zero is the centerline ofeach individual's wrist and numbers refer to elements to the left(negative) and to the right (positive) of the center element (0) whenlooking at the wrist with palm side up. All subjects in this table wereright handed. U=Ulnar, M=medial, and R=Radial.

TABLE 1 Wrist Wrist Subject Circ. Width −7 −6 −5 −4 −3 −2 −1 0 1 2 3 4 56 7  1 15.5 5.2 U U M R R R  2 17.6 6.4 U M R  3 17.5 5.7 U M M R R R  416.5 5.9 U M M M R R  5 18.7 6.6 U U M M R R R  6 15.5 5.2 U U M R R  716.3 5.3 U U M R  8 15.5 5.2 U U M R R  9 17.5 6.5 U U M M M R R 10 15.95.2 R U U M M M R R 11 15.2 5.1 U M M R 12 14.3 4.6 R R R M M U U

Some embodiments of the device have different fixed spacings betweenappropriately sized electrodes to target nerves in patients with varyingphysiology based on wrist circumference. The wrist circumference of 5thpercentile female to 95th percentile male is 13.5 19.5 cm. Sizingdiagrams are shown in FIGS. 5A-5C, which illustrate three bandconfigurations using 22 mm square electrodes. FIG. 5A illustrates anembodiment of a band 500 having three electrodes 502 that are spacedabout 13 mm apart that can be used for wrists with a circumferencebetween about 13.5 an to 15.5 cm. Since 22 mm electrodes were used, thespacing between the centers of the electrodes is 35 mm. The procedurefor determining the spacing is further described below. FIG. 5Billustrates an embodiment of a band 500′ having three electrodes 502′spaced about 18 mm apart that can be used for wrists with acircumference between about 15.5 and 17.5 cm. FIG. 5C illustrates anembodiment of a band 500″ having three electrodes 502″ spaced about 23mm apart that can be used for wrists with a circumference between about17.5 and 10.5 cm.

Sizing of the electrode structure may be based upon a balance of patientcomfort, device power consumption, and ability to target nerves. Smallelectrodes are advantageous because lower currents and power are neededto stimulate a nerve. However the smaller electrodes may have severaldisadvantages, including: (1) increased difficulty of nerve targeting,as the electrode has to be placed precisely at the right anatomicallocation; (2) intensified edge effects of the electrical field producedbetween electrodes, which reduces comfort of the patient; and (3)reduced surface urea of the electrode in contact with the skin, whichcan cause small deviations in the electrode integrity and skin adhesionto reduce patient comfort. In contrast, larger electrodes areadvantageous because they tend to be more comfortable for the patientbecause of the reduction of electrical field edge effects, reduction insensitivity to small deviations in the electrodes, and reduction msensitivity to the current amplitude step size on the stimulator device.In addition, less precise placement is needed for larger electrodes.However, a disadvantage of larger electrodes is the requirement of morecurrent and power to achieve a specified current density.

In some embodiments, wrist circumference and nerve location are theprimary anatomical factors that drive selection of electrode size. Themedian nerve is generally located on the centerline of the ventral sideof the wrist. Therefore, as shown in FIG. 3 for example, an electrode302, the median electrode, can be placed on the centerline of theventral side of the wrist. To target deeper structures and minimize thewidth of a device, another electrode 300, the return electrode or commonelectrode, can be placed on the centerline of the opposite side, ordorsal side, of the wrist. In some embodiments, the median electrode maybe offset from the centerline to be biased towards the thumb while thereturn electrode remains placed on the centerline of the dorsal side ofthe wrist. In some embodiments, the offset of the median electrode canbe a predetermined distance, which is at maximum, about one-quarter ofthe circumference of the wrist. A third electrode, the radial electrode,can be placed in between the first and second electrode to target theradial nerve. Some embodiments can utilize more than three electrodes.For instance, an additional electrode can be added to target the ulnarnerve. In addition, different combination of electrodes can be used totarget one or more nerves from the group of the median, radial, andulnar nerves. In some embodiments, ail electrodes can be the same size(i.e., area) for two reasons: (1) ease of manufacturability at largevolumes, and (2) improved comfort by maintaining the same currentdensity at any pair of electrodes. As shown in FIG. 6, theseconsiderations may set an upper bound for the size of the electrodes 600to stimulate the median nerve 602 and radial nerve 604 as one-quarter ofthe circumference of the smallest person's wrist (5th percentilefemale), or about 3.5 cm.

In some embodiments, the lower bound of the electrode size can be 5 mm,based on the smallest sizes found in literature of electrode arrays.Within these limits, a 22 mm by 22 mm size was chosen because it alloweda good balance between stimulator power and nerve targeting. The 22 mmsize allowed a reasonable amount of misalignment for targeting the nerve(about 1 cm circumferential measured empirically), without consuming anunreasonable amount of power for a wearable device form factor. The 22mm size is also a standard size tor electrode manufacturing as it isused commercially in ECO devices. In some embodiments, the electrodesize can be between 10 mm and 30 mm, or 15 mm and 25 mm, or 20 and 25mm.

Based on electrode size and to accommodate variation in wrist size, theelectrode spacing can be grouped into three sizes in some embodiments,in which each size spans a wrist circumference range of 2 cm. In eachrange, the middle wrist circumference in that 2 cm range was chosen andspacing of the electrodes was calculated based upon the wristcircumference. For example, in the smallest sized bond, for wrist sizes13.5 to 15.5 cm, calculations were based on a 14.5 cm wristcircumference. The center-to-center spacing of the median electrode andthe return electrode on the back of the wrist should be roughly half thecircumference of the wrist. Subtracting the size of the electrodes (22mm) determines that the inter-electrode spacing should be around 13 mm.

Sizing calculations were also slightly biased such that placement of themedian electrode erred towards the thumb, as this was more effective atstimulating tire median nerve and would avoid stimulating the ulnarnerve, in case the electrodes were shifted or placed imprecisely, insome embodiments, ulnar nerve stimulation may be less preferable thanradial nerve stimulation as it was found to cause an unpleasantsensation in early testing.

Test arrays were fabricated by affixing hydrogel electrodes to a linerat the desired distances. The common electrode was aligned to the centerof the back of the wrist and the hydrogels were connected to astimulation device. As shown in Table 2, all subjects were able totarget the radial and median nerves using the appropriately selectedbands. At a shift of 1 cm towards the thumb, most individualsexperienced diminished median nerve excitation that could beaccommodated with greater amplitude of stimulation. At a shift of lenttowards the pinky, many individuals gained ulnar sensation. After alarge shift of about half an electrode pad size, most subjects werestill able to feel the stimulation of the correct nerve, butoccasionally required a greater amplitude of stimulation. Thesepreliminary results demonstrated that the electrode spacing and size wassufficient.

TABLE 2 Data, confirming that the electrode spacings successfully targetthe median and radial nerve of a number of individuals. WristCircumference Hand Gender (cm) Stimulated Size Radial Median M 17.1 R LYes Yes M 17.5 R L Yes Yes M 18.6 R L Yes Yes M 17.5 R L Yes Yes M 17.4L L Yes Yes M 17.9 R M Yes Yes F 16.3 R M Yes Yes M 16.6 R M Yes Yes M16.5 R M Yes Yes F 14.5 R S Yes Yes F 15.4 R S Yes Yes F 14.9 R S YesYes F 12.7 R S Yes Yes F 15.6 R S Yes Yes

In one embodiment of the device, the electrode connections could belocated on the underside of the electronics box, where one type ofelectrode connection could be a snap button. In FIGS. 7A and 7B, allthree electrode connectors 700 are located on the underside of theelectronics box 702. The connectors 700 on the electronics box 702 caninterface with a flexible electrode system 704 which can havecomplementary connectors 706. The flexible electrode system 704 can alsohave three electrodes 708 that are electrically connected to thecomplementary connectors 706 using electrical traces 710. The componentsof the flexible electrode system 704 can be integrated onto a flexibleliner 712. The advantage of this construction where the electrodeconnections are on the electronics box is that electronics are notneeded in the band. The disadvantage of this construction is that theflexible traces 710 may require custom manufacturing and commensurateincreased cost. Additionally, the flexible traces 710 may widen the bandor contribute additional complexity and cost if constructed as atwo-layer flex.

Other Electrode Array Configurations

Various types of electrode arrays can be used. In some embodiment asdescribed above, a circumferential array of two or more electrodes, suchas three electrodes, positioned circumferentially around patient's wristor arm can be used. Other electrode array configurations can also beused, including two dimensional arrays. The electrode pairs formed inthese electrode arrays can be designed such that each element isindividually addressable and has limited current density. This arrayconfiguration is an improvement over conventional dual-element arrays.First, it limits current density spikes that can cause discomfort andthat can increase the risk of burns with larger elements. Discomfort andburns can occur when, for example, hydrogels peel off or dry clothelectrodes have poor contact with the skin. Second, it enables selectingthe optimal stimulation location for each patient's specific geometry orneurophysiology. The stimulation location may be targeted either byexciting a single set of electrodes or by steering the current usingsimultaneous excitation of multiple electrodes. Third, it permitsshifting the stimulation location over time to reduce the overallcurrent density applied to a certain patch of skin which can reduce skinirritation due to stimulation.

In some embodiments, an electrode array may have a defined pattern ofelectrical contacts arranged in a ring around the wrist. In order tostimulate electrically, current can be applied between two sets ofcontacts through the human skin. In this array, any number of electrodescan be connected to either set of contacts, making it very configurable.In most situations, a skin interface will need to be placed in betweenthe electrode contacts and the person. In many cases, the mechanical andelectrical properties of this skin interface coupled with the mechanicalproperties of the array will influence the performance and complexity ofthe device.

Typically for nerve excitation in the wrist, two electrodes 800′ areplaced longitudinally along the nerve with a reasonable spacing of atleast 1 cm, as shown in FIG. 8B. The purpose of this positioning is toget the electric field 802′ to penetrate into the tissue to depolarizethe underlying nerve 804. With two adjacent electrodes 800′, there isonly a shallow penetration of the stimulating current. In contrast asshown in FIG. 8A, with electrodes 800 excited on opposite sides of thewrist, the electric field 802 extends through the wrist and this enablesexcitation of nerves 804 deeper in the tissue. As shown in FIGS. 4A and4B, to achieve the same level of stimulation using longitudinally placedelectrodes, would likely require a larger cuff. Therefore, thecircumferential array is compact and thus advantageous for wearabledevices. The advantage of having the configurability of the array isthat the same nerves can be reached, but in a more compact form factorthan convential median nerve excitation.

The circumferential array structure addresses issues of sizing. In someembodiments as shown in FIG. 9, the flexible array 900 of electrodes 902could be made in a one-size-fits-all fashion and placed around anyindividuals wrist. However, electrodes 902 that are not used are simplynot addressed by the stimulator. This allows one size to be customizableto a large population.

The array design is defined by the 1) center to center spacing, 2) theinterelement spacing, and 3) the shape of the electrode, and 4) theelectrical and mechanical properties of the skin interface, typically ahydrogel. In some embodiments, for wrist-worn treatment of tremors thearray 900 has a center to center spacing of about 1 cm, an interelementspacing of about 2 mm, and rounded-corner rectangular elements such as 2mm filet. Since the array 900 can conform to the body, the contacts canbe fabricated as an electrically conductive Ag or Ag/AgCl trace 904 on aflexible polyester substrate 906, though other trace and substratesmaterials could be used such as gold plated copper on polyimide. Asingle strip of hydrogel with a reasonably high volume resistivity(−2500 ohm-cm) can be applied across the array and used to contact theskin. The selection of these parameters is determined by the desiredrange of anatomical sizes, electrical characteristics of the skininterface, sensation of stimulation, duration of stimulation, andpermissible complexity of the electronics.

In some embodiments, the device is designed to minimize cross talkbetween elements/electrodes. Cross talk causes adjacent areas to bestimulated and can lead to draining power or increasing off-target sideeffects of the stimulation. Cross-talk can be minimized by selecting ahydrogel with a high volume resistivity to discourage current spread inthe lateral direction and limit the effective area of stimulation. Withlower volume resitivity, current spreading could prevent the ability tospecifically target individual nerves. In addition, larger resistivityhydrogels tend to decrease edge effects and increase comfort ofstimulation. However, a volume resistivity that is too large willconsume more power, which increases demands on the electronics and thesize of the battery. In some embodiments, an intermediate resistivitycan be chosen in order to balance these competing needs. Additionally, asmall amount of current spreading could also be beneficial to patientcomfort as the current density will taper off more gradually.

Cross-talk could also be regulated by modifying the shape and theinterelernent spacing. For instance, decreasing the area of theelectrodes 1002 (FIG. 10) in the array 1000 can help limit the excitedarea compared to FIG. 9. Modifying the center to center spacing can alsolimit the overlap area of neighboring elements/electrodes.

Changing the electrode shape can also control the excitation in an areaand make the stimulation more comfortable. In the case of rectangularelements, often the corners show an increase in current density, whichcan lead discomfort. In some embodiments, a circular element/electrode1102 (FIG. 11) can be chosen to increase comfort.

A further approach to reducing cross-talk is to separate the hydrogelpieces and eliminate current flow from pad to pad. However, thisincreases the complexity of the manufacturing process.

In some embodiments as shown in FIG. 12, the electronics and electricalcircuit 1200 used to drive the array include an adaptable switch thatallows each individual electrode 1202 to be connected to either one ofthe two contacts 1204, 1206 of the stimulator 1208 at a given time byopening or closing switches 1210 in each channel. Each channel caninclude a DC blocking circuit 1212, as charge balance is important toprevent skin irritation and burns, and also be individually currentlimited by current limiters 1214 in order to prevent current surges thatcould cause injury or discomfort. This current limitation can be set toa predetermined tolerability threshold for a particular patient or groupof patients. There are many transistor circuits or components likepolyfuses known in the art to limit or shutdown the current to aparticular node. These circuits and its components, such as thestimulator, switches, and current limiters, can be controlled and/or beprogrammable by a microprocessor 1216 in real-time. The switch matrixallows multiple electrodes to be connected to the same stimulatorcontacts at a given time for maximum flexibility. In addition,electrodes can be switched between the positive and negative contacts ofthe stimulator to produce a bipolar pulse, as described below.

Another benefit of the array geometry is to map the physical layout ofunderlying neurophysiology. This could be used to tune the stimulationappropriately for each subject. For example, the array elements could beused to map the underlying muscle firing (electromyography) or theunderlying nerve activity (electroneurography). This information may beused in a closed-loop system to monitor the tremor or optimize thestimulation over time.

Expanding the underlying concept to the circumferential array describedto a finer microarray offers significant advantages for stimulation. Astructure that is a material with miniature, current-limited arrayelements would solve problems with current spikes or electrode peeling.Designing the microarray is a balance of a need for high lateralimpedance to prevent crosstalk and low impedance for efficient powertransfer from the stimulator. As shown in FIG. 13, such a microarray1300 could be a woven fabric or a series of conductive elements 1302 inan insulating polymer to create a uni-axially conductive geometry.

There are advantages to using a microarray instead of a conventionalelectrode system in order to maintain comfortable and safe stimulationin situations when the adhesion to the skin is compromised. Twosituations generally cause pain and burns to a patient, electrodepeeling and breakdown of electrode material; both are associated withincreases of current density. In a conventional electrode system, asshown in FIG. 14A, current I 1400 is applied to a single electrode 1402of area A attached to the skin 1404. The current density is then J=I/A.As the electrode peels 1406, as shown in FIG. 14B, the area A decreases,which increases the current density, J. The current density couldincrease to a point where the patient becomes uncomfortable orexperiences side effects on the skin.

In a matrix array with regulated current density, however, the currentdensity can be regulated to prevent discomfort. In FIG. 14C, the largeelectrode area is divided into an electrode array, with smaller elements1408. Each element has an associated current limiting circuit 1410 thatlimits the current to a value that is comfortable 1412. Because thesecurrent limiters exist, in FIG. 14D, even when some of the arrayelements peel 1414 and zero current flows through those elements 1416,the current through all the rest of the elements 1412 is still limitedto a level that is comfortable.

A second common situation where the microarray offers advantage over aconventional electrode system is when one area of the electrode isshorted due to a breakdown in the material or the mechanical nature ofthe material. In a conventional electrode system as shown in FIG. 15A,current I 1500 flows through an electrode 1502 on the skin 1504. In FIG.15B, if a short circuit 1506 occurs in the electrode for example becauseof a defect or another reason, the whole current I 1500 flows throughthat single point, which could cause discomfort. In FIG. 15C, a multielement array has current limiters 1510 connected to each array element1508. An example of such a current limiter is a very large resistor, R,much larger than that compared with the resistance, r, of the electrodeitself 1508 (i.e., R>>r). In this case, the current through each elementis roughly the total current divided by the number of elements. In thecase where a short 1506 occurs in one element, since R>>r, the currentthrough each element 1514 is still roughly equal to the total currentdivided by the number of elements.

The two situations described would be particularly problematic fornon-adhesive electrode configurations. For example, conductive fabricsmay intermittently only contact one small region of the skin and causeall the all the current to flow through a small area at high currentdensity. One solution to this problem is the embodiment of anon-adhesive array depicted in FIG. 16. This embodiment uses a series offine pins or balls 1600 connected to a flexible substrate 1606, likecloth, to form the microarray of electrodes. Another material like aconductive foam or a comfortable layer 1602 can be added between theballs and the skin to address any discomfort, providing that the lateralresistivity is relatively higher compared to the through resistivity.This solutions minimizes the cross talk between the contacts. Such amicroarray of elements/electrodes can be constructed as a matrix ofmultiple electrodes mechanically connected and each having their owncurrent limiting circuit 1604. Electrodes in the matrix could be groupedinto larger subgroups of elements that are individually controlled 1608and 1610. Another option is to use a woven fabric where the resistanceof each wire limits the current.

Patterned Stimulation Alternating Between Nerves

One aspect of the device is the patterned waveform used to stimulatemultiple nerves. This waveform uses alternating bursts of higherfrequency stimulation (typically 50 Hz 2 kHz) and 50 μS-1 mS pulse widthon peripheral nerves that map to adjacent locations in the brain. Thistype of stimulation may desynchronize the neuronal populations andrestore normal function. These burst patterns match certain tremorcharacteristics of the patient, including the phase, frequency andamplitude of the tremor. In one implementation, where the median andradial nerves are used to treat tremor, pulse trains at 150 Hz frequencyand 300 μS pulse width) are a length that is just under half of thetremor period and alternating between the two nerves. FIG. 17illustrates a typical patterned waveform stimulating median and radialnerve used to treat tremor. Each burst is formed from pulses at a higherfrequency and an appropriate pulse width for targeting the right typesof nerves. The bursts alternate with timing relating to the patient'stremor frequency. Each burst is up to half of the tremor period suchthat the bursts are non-overlapping and the bursts are time-shifted byhalf the tremor period such that the alternating cycle is repeated witheach tremor period.

There are several variations on this stimulation, including stimulatingmore than two nerves as shown in FIG. 18 and changing the ordering ofpulse trains as shown in FIG. 19. If the number of stimulated nerves isincreased to N, the maximum burst length of each pulse train will be 1/Ntimes the tremor period such that the bursts are non-overlapping. Theburst on the second nerve will shifted 1/N times, the burst on the thirdnerve will be shifted 2/N times, up to the final nerve N that is shifted(N-1)/N times the tremor period.

The order of the pulse trains on different nerves can be randomized asshown in FIG. 19, The upper limit on the length of the bursts is 1/Ntimes the tremor period and the order of the bursts on the three nervesis randomized. However, all three nerves still experience a single burstof stimulation within a length of time equal to the tremor period, asillustrated by each white or gray section, in subsequent intervals oftime equal to the tremor period, the order of the burst pattern on thenerves is again randomized.

There can be pauses at different times in the sequence. These pauses canbe regular or occur at random times. The pauses may help with thedesynchronization and also have the side effect of increasing thetolerability of stimulation because less power is generally transmittedto the hand. Less power transmission also reduces the power consumptionfrom the battery and can help reduce the overall size of the wearabledevice. FIG. 20 illustrates a waveform pattern showing pauses in thestimulation. Each group of stimulation bursts is grouped in timeintervals equal to the period of tremor. At regular times, stimulationcan be stopped or paused for one or more segments equal in length to theperiod of the tremor.

While the embodiments described above have used constant 150 Hzstimulation as an example, the waveform within each burst can vary inamplitude, timing, or shape. For instance, in some cases, radial andmedian nerve amplitudes need to be changed since one nerve may be moteeasily excited than the other based physiology or hand position. Theamplitude during the burst can also be varied, for example sinusoidally.The pulse width and frequency inside a particular burst pattern can alsovary, for example, a stochastic resonance electrical stimulation patterncould be used to choose a random distribution of the pulse width andfrequency of a certain square pulse. Stochastic resonance has been shownto enhance sensory perception and feed back into the central nervoussystem.

The electronics implementation of this alternating waveform isadvantageous because only one stimulator is needed since only one nerveis stimulated at any given time. This is enabled by the switch matrixdesign described above and illustrated in FIG. 12. The advantage of theswitch matrix design is that it helps achieve a safe design that reducesthe size and cost of the device, characteristics essential for awearable device. The specific advantages include:

Utilization of only one stimulator since only one nerve is excited at atime. This reduces the size and cost of the device by reducing theamount of electronic components required, compared to other techniquesthat need multichannel stimulators.

The switch matrix allows every electrode in an electrode pair to beassociated with its own protection circuitry. This protects against anysingle point failure in the matrix. For instance, if a DC blockingcapacitor is associated with every electrode, even if one of thecapacitors failed, the patient would still be protected from DC currentsfrom the second capacitor, as shown in FIG. 12.

Additionally, the switch matrix minimizes or reduces the number of highvoltage rails needed for biplasic stimulation, which reduces the numberof components in the device. Instead of creating both negative andpositive rails, a single voltage rail and ground rail are created. Byconnecting alternating electrodes to the ground rail or the high voltagerail, the biplasic waveform can be created as shown in FIG. 21. As shownin FIG. 21, two voltage lines, a high voltage line 2100 and a groundline 2102 are created, and electrodes 2104 are alternately connected toeach voltage line to produce the biphasic waveform 2106. Reducing thenumber of components translates to space and cost savings that arecritical to a wearable device.

Device Fitting For Electrode Arrays

In some embodiments, a manual fitting procedure can be used. In a manualfitting procedure, the device can be placed on the patient's arm. Eachindividual electrode can be switched on and stimulation applied. Thelocation of paresthesia can be noted for each electrode location andcorrelated to a particular nerve by using information found inliterature. For example, if a particular array element causesparesthesia in the thumb, index, and third finger, then that electrodestimulated the median nerve. Ulnar and radial nerves can be found insimilar ways. The operator can then program those nerve locations andcorresponding associated electrodes into the patient's device. Thedevice can recall these locations to provide consistent therapy to aparticular individual, provided that the band and electrodes areconsistently placed on the patient's wrist at the same location andorientation. To aid repeatable placement on the wrist, visual ormechanical markers that line up with anatomical features can beemployed. One example is to curve the box to fit the curve of the wrist.A second example is to make the device watch-like, with intuitivepreferred orientation. A final example is to provide visible indicators,like marks or lines that can line up with corresponding anatomy, likethe tendons of the wrist or the bones on the hand and wrist, such as theulnar styloid process.

In some embodiments, the fitting procedure can be automated usingfeedback from on-board sensors. For instance, one may use ring receivingelectrodes 2200 on the fingers similar to those used in carpal tunnelnerve conduction studies. These receiving electrodes 2200 can be used tomeasure whether stimulation of a particular electrode 2202 placedcircumferentially on the wrist or arm causes a measurable response 2204in a target nerve 2206, such as the median, radial, or ulnar nerve, asshown in FIG. 22. This can also be used in some embodiments to confirmthat a particular nerve, such as the ulnar nerve for example, is notstimulated, which can be accomplished by placing a electrode at a fingeror other location that is innervated by that nerve. When the correctelectrode(s) are stimulated, a response can be measured by the ringelectrode on the finger or another electrode, placed at known locationswhere the target nerve innervates.

In some embodiments, fitting can be determined by measuring the responseto stimulation. For instance, if stimulation at a particular locationleads to greater tremor reduction than stimulation at another locationthe device will be directed to stimulate the more effective location.

In some embodiments, during the fitting procedure, the search for thecorrect set of electrodes does not have to be done in a linear fashion.Depending on the person's wrist and width size, there can be a prioriknowledge to the approximate locations of certain nerves. For instance,the median nerve is generally located close to the center line of theventral side of the wrist, and therefore electrodes at that location canbe preferentially tested.

While selecting individual elements is the most direct way of selectinga single nerve, more complex current patterns can be used to shape thecurrent density through the limb. The combination of which electrodes tobe used to excite a particular nerve can be straight forward or morecomplex in order to current steer for the purpose of improving comfort.For example, in FIG. 23A a simple configuration is achieved byconnecting electrodes 2302 and 2304, on opposite sides of the wrist, toa stimulator 2300. Field lines 2306 excite nerve 2308. Another way ofexciting nerve 2308 can be seen in FIG. 23B. Electrodes 2310, 2312, and2314 are selected and connected to the stimulator. The amount of currentpassed through each electrode can be different in order to steer thefield lines 2316. In other configurations, the current density could bereduced in order to make stimulation more comfortable.

A circumferential array is advantageous because array elements can bedynamically selected to change stimulation as necessary. For instance,in some cases, as the position of a person's limb moves around, theposition of a nerve can change. In this situation, a different set ofelectrodes than the original pair may target the nerve more precisely orefficiently and it is advantageous to apply an algorithm to change theset of electrodes used for stimulation.

Dynamic Stimulation Algorithms

In addition to the effective positioning of the electrodes around thepatient's arm or wrist, in some embodiments the electrical stimulusdelivered to the nerves through the electrodes can be improved invarious ways, including for example determining various characteristicsof the tremor and using this data as feedback to modify, adjust and setvarious stimulation parameters as shown in FIGS. 24A-24F and describedin more detail below.

Dynamic algorithms can also help stimulation comfort and reduce rednessor rash. If multiple elements target specific nerve or nerves ofinterest, the signal can be switched between these different elements inreal-time. This may alleviate the irritation at a particular location ofthe skin by reducing the time of stimulation at a particular location.However, the total net effect of therapy will be the same.

Tremor Phase Feedback

In some embodiments as shown in FIG. 24A, the tremor signal, measured byaccelerometers, gyros, or other means like EMG, can be used for directfeedback. For example, using the gyroscope signal allows the angularspeed of the hand to be measured, and thus the angle of the hand can becalculated. It has been shown that responding out of phase to the tremorcan be effective in reducing tremor. Detecting and responding to thephase delay 2402 can be accomplished in hardware or software.

To utilize tremor phase feedback, the signal from the motion sensor canbe integrated, or a combination of sensors can be used to form a signalthat is reflective of hand position. For example, position andorientation can be determined by integrating accelerometer or gyroscopesignals, or by combining the accelerometer, gyro, and magnetometer datato produce a quaternion showing the orientation of the hand. Bycombining the positions in one or more axes, it is possible to produce asignal used for dynamic feedback.

One algorithm of calculating the triggers for the stimulation identifieswhere the derivative of the signal changes sign to find peaks in thesignal. The signal may be noisy, so a filter or threshold may berequired to eliminate noise oscillations. Finally, peaks usually do notoccur faster than the typical tremor frequencies (4-12 Hz), so pointsthat are too close together can be eliminated. From the peaks, theinstantaneous frequency of the tremor can be calculated by looking atthe difference in time between the two peaks. Then, using thisfrequency, the appropriate time delay needed to stimulate out of phasecan be calculated, accounting for the delay in the neural signal fromthe peripheral nerve to the brain. The calculation is done and real-timeand can be adapted to the instantaneous frequency and phase of thesignal.

An alternative approach would be to detect zero crossings or any otherrepeated value in the position or biological signal. However, zerodetection can be challenging due to the tendency for noise around zero.

An alternative approach to detecting phase is to use the real-timeHilbert transform. The Hilbert transform will calculate the envelope andphase from a real-time signal. The instantaneous phase can therefore beused to time the stimulation appropriately. However, the Hilberttransform is complex and challenging to implement on a standardmicrocontroller.

Tremor Amplitude Feedback:

In some embodiments, tremor amplitude feedback modulates the duty cycleof the treatment based upon tremor severity. Tremor amplitude can bedefined and determined in a number of ways as shown in FIGS. 24B and24C, including: (1) maximum or root-mean-square flexionextension/position, velocity, acceleration, or jerk of the hand motion;or (2) the spectral power at a frequency or spectral energy in the 4-12Hz band. Determining maximum hand motion can become computationallyexpensive because of the three-dimensionality. In some embodiments, thesignals from all axes in the gyroscope or accelerometer can beintegrated and the axis with the largest amplitude can be taken todefine the amount of flexion and extension. An alternativeimplementation is to calculate the orientation of the hand from acombination of sensor inputs, and the axis-angle rotation from theneutral position of the hand at an instantaneous point in time can becalculated to specify the degree of flexion/extension. If the envelope2404 of this oscillatory signal is larger than a threshold 2406, therapycan be applied.

This approach may be computationally intensive and it may be preferableto calculate the spectral energy in the 4-12 Hz band for a short timesignal. If a multi-axis accelerometer, gyroscope, or other motion sensoris available, the spectral density can be calculated individually foreach axis and then the L2 norm can be found. The L2 norm could also becalculated prior to finding the spectral density depending on thesensors used. The spectral density can be calculated using a variety ofnumerical approaches 2408 taking the signal from the time domain tofrequency domain, including FFT, welch or periodograms, or using a moremicrocontroller friendly Goertzel tone detection algorithm, all of whichare well known in literature. If the energy under the curve 2410 islarger than a threshold, therapy can be applied.

One difficulty of this feedback mechanism is determining the thresholdat which therapy should be applied. In some embodiments, the thresholdcan be set based upon the actual angle of the hand; surveys and patienttests can determine the acceptable angle ranges for performing dailytasks, like drinking or holding a spoon. The same can be done forspectral density. In some embodiments, this threshold can be set asuniversal across all patients

In some embodiments, the threshold may be individualized to a particularpatient or group of similar patients. This could be done by monitoringthe patient's tremor level (e.g., energy or position) over time anddetermining the maximum and minimum values for the person in a normalsituation. These values could also be recorded over time. Alternatively,the tremor threshold can be denned as a fraction of the minimum value oithe tremor.

In some cases, including Parkinsonian tremor, there may be a habituationto stimulation and the tremor will start to increase again after a shortperiod. Detection of an increase in tremor severity can be used tomodify amplitude, phase, frequency, waveform, or pulse train of thestimulation to improve efficacy and durability.

Tremor Frequency Feedback

In some therapies as shown in FIG. 24D, the frequency of the tremor isused to set the cycle of nerve excitation. For example N units in tiresame neural cluster innervated by N peripheral nerves should bestimulated at a time separation equal to the period of the tremordivided by the N. Since the frequency of the tremor dries not changerapidly, as described below in the section on TREMOR DETECTION, samplingat minute intervals should be sufficient for tracking the tracking. Thespectral density as a function of frequency will need to be calculatedusing the numerical approaches 2408 described above. If there aremultiple axes, their spectral densities can be combined, for example,using an L2 norm. The peak frequency 2412 in the spectral density curvecan then be used to time alternating bursts of stimulation between thenerves.

Predictive Adaptation

A patient's tremor amplitude and frequency can have daily patterns, insome embodiments as shown in FIGS. 24E and 24F, understanding historicaltremor measurements and five time therapy was applied can inform therapyneeded on successive days. Neural networks, Kalman filters, and othersuch predictive algorithms can be used to predict when tremor willincrease and apply pre-emptive treatment.

In addition, long term data collection over the span of months or yearscan provide information on disease progress and the need to adapttherapy. For instance if a person's tremor has been getting worse withthe same degree of therapy, if increasing amounts of therapy are neededto maintain the same overall effect, it may be desirable to modifytreatment.

Often a user has external information that can be used to preventtremor. For instance, tremor is often brought on by stressful events,such as presentations and meetings. Since many patients with tremoralready schedule these events, for example in a calendar, the calendarcan be used to inform prediction of when treatment may be needed. Forinstance, if a patient has a meeting scheduled for 1:00 pm, the devicemay pre-emptively start stimulation at 12:40 pm. A patient could alsoactivate the therapy using a button if suddenly stressed.

Big Data Approaches

As shown in FIGS. 25A-25C, treatment modification can also be determinedthrough the use of big data analytics which can utilize long-termmonitoring of broad populations. Demographic information about eachindividual as well as tremor characteristics (e.g., the degree ofpostural, resting, and kinetic tremors) can be used to categorize peopleinto different subtypes. FIGS. 25A and 25B depict the diseasesegmentation by separating kinetic tremor characteristics of essentialtremor from resting tremor characteristics of Parkinson's disease. FIG.25C depicts the long-term tracking of changes in an individual's tremorseverity. Recommendations on different types of treatment can be made tonew patients in the subgroups, similar to Netflix's approach ofrecommending movies based on the user's similarity to other users. Thistechnique could be implemented using principal components analysis,k-means clustering, or other well-known numerical segmentationapproaches.

All the above forms of adaptation, feedback, and external information,like cloud data, can be integrated together to enhance treatment. FIG.26 shows a flow chart of such a system. In step 2600, sensors can beused to detect motion, position or other biological signals over time.In step 2602, a processor can receive the sensor data and calculatevarious metrics, such as tremor amplitude, phase or frequency. In step2604, the method and system can obtain past history data, and in step2606, external information, such as data from the cloud, can be sent tothe processor of the device; cloud data can include population deriveddata, calendar data, and input entered into the device. The processorcan combine all this data in step 2608 and can adjust the stimulationtreatment and parameters in step 2610 based on this combined data. Themethod and system can then loop back to step 2600.

Amplitude Setting

The aspect of the design is the method of how optimum amplitude ofstimulation is identified and reached during a session. This method isimportant towards the comfort and efficacy of the treatment. Theperception of stimulation differs among patients and circumstances. Forinstance, an instantaneous increase in amplitude directly from 0 mA tothe optimum stimulation level can cause an uncomfortable sensation. Aslower increase of stimulation can be more comfortable, but a wearer'sperception of the amplitude of stimulation may not be linear withapplied current amplitude. If there is a long period where the wearerhas no perception of stimulation, for instance if the device rampslinearly from zero amplitude, the wearer may even think the device isbroken.

Two subjects were studied in an experiment to understand the perceptionof stimulation level. Electrodes were positioned to target the medianand radial nerves separately. During the session, the stimulation wasramped slowly at 0.1 mA increments to identify the sensation threshold,muscle contraction threshold, and discomfort/pain threshold. After thesepoints were identified, the subject was allowed to rest for severalminutes until the sensation of tingling went away. Then, the currentamplitude was ramped from the sensation threshold to 85-90% of thestimulation threshold of muscle contraction or discomfort/pain,whichever occurred at the lower amplitude. At each step, subjects wereasked to shade a drawing to see where the paresthesia was felt and alsomark on a visual analog scale (VAS) how intense they felt thestimulation compared to the maximum level they felt previously. Thedistance of their marks on the VAS were then tabulated and normalized tothe length of the VAS marker.

Both subjects reached a muscle contraction threshold (i.e., when theyfelt their hands were heavy and difficult to move) before severediscomfort. Results are shown in Table 3. This result suggests thatamplitude for median and radial nerves are different and potentiallyshould be adjusted separately to achieve optimum stimulation for bothnerves. In both subjects, the radial nerve could have been stimulated atmuch higher amplitudes to achieve a greater effect

TABLE 3 Results of stimulation thresholds for two subjects to understandthe relationship between sensation and stimulation amplitude. RadialRadial Median Median sensation muscle action sensation muscle actionthreshold threshold threshold threshold (mA) (mA) (mA) (mA) Individual 12.5 4.7 3.1 5.4 Individual 2 2.2 5.4 2 4.7

A great degree of habituation and hysteresis were observed in thesensation of stimulation, as shown in FIGS. 27A and 27B, which show therelationship between patient sensation and stimulation amplitude for twosubjects. When increasing stimulation towards the 85-90% level of themaximum sensation threshold, the individual showed a steep,nearly-linear rise between the level of first sensation and the maximumlevel. However, when stimulation was decreased, perception of thestimulation intensity had a slope that dropped more rapidly than duringthe increase in amplitude.

This result indicates that the stimulation ramp could be fairly linearbetween the threshold of first perception and 85-90% of the maxstimulation level (from discomfort or muscle contraction). The rampshould not start linearly from zero, because the first perceptionoccurred at amplitudes half of the max threshold. Thus, if the ramp isslow and linear from 0, for half the time of the ramp, the patient mayfeel no sensation. Another stimulation could be exponential to reflectthe exponential appearance of the radial nerve measurement forIndividual 1. FIGS. 28A-28D illustrate various ramp types. FIG. 28Ashows that the measured data suggests a linear ramp rate between thefirst sensation and max motor contraction/discomfort threshold wouldwork in terms of constant perception of the amplitude. FIG. 28B shows anexponential increase, which could have to occur if the patient becomeshabituated to the stimulation. FIG. 28C illustrates a periodic waveformshowing the amplitude ramping up and down to different maximumamplitudes. A patient may become more habituated as the waveformamplitude is gradually increased, so a higher treatment amplitude may betolerated by the patient. FIG. 28D illustrates another method forachieving higher treatment amplitude, which is to surpass or actuallyreach the level of discomfort on the first ramp up; in this way thepatient could become immediately or rapidly habituated and be able towithstand higher stimulation during the treatment time.

Also, because of habituation and hysteresis, if a higher stimulationlevel affords greater efficacy, in some embodiments, the waveform can bea series of smaller ramps that increase stimulation level, with eitherpauses or a small decrease in level between each ramp as illustrated inFIGS. 29A and 29B, which will allow an individual to have a higherstimulation amplitude with less discomfort.

Tremor Detection

As discussed above, adaptively modifying the stimulation may requiredetecting tremor characteristics by processing one or more motionsensors, such as different multi-axis sensors. FIG. 30 is a flow chartof how tremor frequency can be calculated from motion sensors. It isadvantageous to use multi-axis motions sensors over single-axis sincetremor motion does not always occur along the same direction, especiallyif different actions are being performed. For instance a 3-axisgyroscope can be used to measure the tremor from the wrist. Each axis isthen individually windowed and the Fourier transform is applied. Themagnitude of each axis is then calculated and the square root of the sumof the squares of the axes are calculated as a function of frequency.The summed spectrum is then smoothed with a box car filter or other lowpass filter, and the peak frequency in the 4-12 Hz range is identified.The frequency may be detected by determining the frequency at themaximum value in the 4-12 Hz range. However, as depicted in FIG. 31A, insome cases the boundary artifacts from processing may be falselyinterpreted as a signal maximum. One approach shown in FIG. 31B is tofirst do an aggressive band pass filter from the 4-12 Hz band prior totaking the FFT. A second approach is differentiate the curve and findthe zero crossing points, then from that subset of zero crossing pointsfind the frequency value with the maximum spectral amplitude. Gyroscopesare generally preferred for spectral analysis since they typically donot have the DC offset of accelerometers.

In some embodiments, the frequency can be updated sporadically (versuscontinuously) because the timescale of frequency shifts is long. This amajor advantage over devices requiring real-time responsiveness as it isa significant simplification that leads to smaller battery sizes,improved form factor, and the ability to measure tremor from highquality sporadic data instead of requiring continuously high qualitytremor extraction from real-time data. FIG. 32 shows data from anindividual with tremor wearing an inertial measurement unit (IMU) over aday, where the tremor frequency does not vary dramatically. The meanfrequency was 5886 Hz and spread of frequency varied over 1.6 Hz.

In some embodiments, the frequency of the tremor is measured from thewrist. While tremors are typically measured at the hands, as shown inFIG. 32 the wrist and hand gyro frequencies track each other well andare well correlated. The average difference between the hand and wristgyroscope was 0.076 Hz with a maximum deviation of 0.8 Hz, which is wellwithin the spread of frequency variations within the day. Measuringtremor from the wrist has major advantages over devices requiringmeasurement on the hand as it can be done with watch-like form factors.In a device targeting the median, radial or ulnar nerves in acircumferential band on the wrist it implies that the sensors formeasuring tremor can be on-board the same device used for stimulation.

In some embodiments, the tremor period can be measured from mechanicalinputs using gyroscopes, accelerometers, bend sensors, pressure sensors,etc. from the back of the hand, wrist, or any part of the limb thatexhibits tremor.

In some embodiments, the tremor can be measured via EMO or otherelectrical signals.

In some embodiments, the tremor frequency can be measured at all timesand then used to update the stimulation in real time.

In some embodiments, the tremor frequency can be calculated only insituations where it is appropriate. For instance, looking at the band oflower frequencies or other patterns in the spectrum, certainmeasurements can be eliminated due to confounding voluntary activity.For example, FIG. 33 illustrates frequency spectrum analysis from aperson with no tremor while jumping. The results of this analysis couldclearly be mistaken for tremor, but patterns of high frequencies can beidentified and used to eliminate certain activities or combined withsensor measurements to predict behavior.

One aspect of the system and method is differentiating tremor movementfrom non-tremor (or voluntary) movements, or detecting activites knownto produce tremor to selectively measure tremor. FIG. 34 shows ananalysis of 32 activities performed with and without tremor. Using theenergy in the voluntary band (0.1-3 Hz) and tremor band (4-12 Hz), alogistic regression model was created that could segregate tremor versusnon-tremor activities.

Band

As shown in FIG. 35, one aspect of the device 3500 is a band 3502 tosecure the stimulation device to the wrist. The band also connects twoelectrodes back to the device housing 3504 via a flexible circuit 3506.In other embodiments, the band may connect more than two electrodes backto the device housing.

In some embodiments, the electrodes (not shown) are removably recessedinto pressed and perforated neoprene 3508 using a snap socket 3508 tocreate a comfortable seal between the band and skin, as drawn in FIG.35. This seal also preserves the disposable hydrogels electrodes thatconnect to the patient's skin. The band can be vented by perforating theneoprene.

In some embodiments, the band lengths can be designed such that thefirst side fully houses and connects the electrodes that are positionedto target the median and radial nerves. The band length of the oppositeside can be between about 10-13 cm to make it easier to fasten thedevice to the wrist for wrist sizes of 5 percentile female to 95percentile male.

In some embodiments, the band is flexible to comfortably conform to thewearer's wrist, and allows the band to lie flat on a surface to makeinstallation and removal of electrodes more convenient.

Riveting the electrical flex circuit to the band using an electricallyconductive eyelet and snap is a process that secures the circuit inplace and provides an electrical connection for the removable hydrogelelectrodes.

In some embodiments, the band can be made of foam and neoprene and canaccommodate three single electrodes. Recessed electrodes allow for amore comfortable fit and a more compact form factor.

As shown in FIGS. 36A-36C, one embodiment for the band 3600 incorporatesan adjustable ring or buckle 3602 in combination with a snap or buttonfastener 3604, which allows the wearer to adjust the tension of the band3600 after it has been secured to their arm/wrist.

One aspect of the device are removable hydrogel coated electrodes thatsnap into the band and electronics housing. These electrodes a placeddirectly on the wearer's skin for a secure, robust electrical connectionto prevent loosening or peeling during normal usage, which can causepain or discomfort.

One embodiment of the electrodes 3700 has tabs 3702 that are not stickyto allow for easier installation and removal of the electrodes from theliner during installation and then from the band and housing duringremoval, as shown in FIGS. 37A and 37B. As an example, the non-stickytabs may be approximately 1/16 inch on a ⅞ inch square electrode tominimize wasted space while enabling easy grasping. The electrodes 3700can have a snap fitting 3704 than can be inserted into a snap socket inthe band. The electrically conductive film 3706, which can function tospread current, and the stimulation gel 3708, such as an electricallyconductive hydrogel, can coat the skin facing side of the electrode. Afoam or cloth backing 3710 could be used to provide a non-sticky sidefor easy handling by the patient, in other embodiments, the double-sidedstickness of the hydrogel is used to adhere directly to the band. Insome embodiments, the connector 3712 may include a conductive eyelet andsnap, wire, or other standard connector.

One embodiment of the electrodes has three electrodes 3800 spaced on athin, plastic liner 3802 with a spacing that corresponds to theelectrical snaps on the band and housing, which allows for easier andquicker installation, as shown in FIG. 38.

One embodiment of the electrodes has a backing made of a neoprene foam,which provides an a stiffer, non sticky surface to enable easier removalfrom the backing liner during installation. One embodiment of theelectrodes has three electrodes 3900 spaced on a thin liner 3902 allconnected with a single foam backing 3904 to make it easier to removeand discard the electrode after wearing, as shown in FIGS. 39A and 39B.In another embodiment, the foam backing 3904′ connecting the electrodes3900 is serpentine shaped to allow small movement between theelectrodes, as shown in FIG. 40C.

As shown in FIGS. 40A and 40B, one aspect of the device is a cradle 4000or support mechanism in the packaging that holds the electronics housing4002 and bund 4004 so that it is easier to install and remove theelectrodes 4006 and plug into the USB charger 4008. Since the housing ofthe device is curved, the cradle makes it easier for the device to bestable during these activities.

One aspect of the design is the location of the electrodes relative tothe electronic housing to better target nerves at the wrist. Theelectrode and band 4100 in the housing box 4102 are shifted off-centerdistally (i.e., towards the hand) to allow for better targeting of thenerves. By moving the electrode placement distally on the arm thestimulation will more likely activate nerves instead of muscles, asshown in FIG. 41.

One aspect of the design has button locations that allow the wearer tomore securely brace their hand when pressing a button 4200 by designingthe housing with broad, flat surfaces 4202 on the opposite side of eachbutton 4200, as shown in FIGS. 42A-42D. FIG. 42A shows a bracinglocation for targeting buttons at distal end of the device. FIG. 42Bshows a bracing location for targeting button on side of the device,FIG. 42C shows a user bracing and targeting a distal button, and FIG.42D shows a user bracing and targeting a side button. This aspect of thedesign is important to improve usability of the device fora wearer withtremor that have difficulty with targeting tasks.

One aspect of the design is a curved electronics housing that followsthe shape of the arm and wrist, which allows for more consistent andeasier positioning of the device when being applied by the wearer.

Alternative Form Factors

One concept for simplifying the process of placing the device is tocombine the electrodes into one adhesive patch. In order to target anyof the nerves, the electrodes have been lengthened to fit the width ofmost adults. FIG. 43 shows one embodiment of such an electrode 4300. Onthe skin side, two conductive regions that may have a carbon or silverbacking to improve conductivity nave a conductive hydrogel layer 4302used to adhere and form a good contact with the skin. There is anonconductive region 4304 in the center which may have no adhesive orsome nonconductive adhesive. Note that around the hydrogel is an acrylicadhesive 4306, for example, used to maintain contact with the skin andprovide shear strength. The adhesive also maintains a seal to preventthe hydrogels from drying out. The backing of the electrode ispreferably a breathable material, like a nonwoven mesh. The backside ofthe electrode attaches with connectors 4308 to the device or band toallow the electrical stimulation device to be interfaced to thehydrogels. This interface could be done in multiple ways, includingusing an adhesive with conductive lines to interlace with metal contactson the band or device, or using straps on the electrodes that can besnapped in to a conductive mating piece on the band or device.

If multiple nerves are targeted with the approach above, the band mayrequire multiple interfaces to the electrode to accommodate varyingnerve positions. Using snaps may require sliding components toaccommodate individual differences in the nerve spacing, which may beaddressed using conductive lines. An alternative approach would be tointegrate multiple electrodes into one patch and offer patches with awide variety of dimensions to accommodate different hand sizes and nervepositions.

FIGS. 44A-44C demonstrate embodiments that simplify the band 4400 byusing the stickiness of the hydrogels to facilitate placement. Insteadof having a watch-like interface, where both straps are floppy anddifficult to place, the adhesiveness of the electrode can be used toenable one-handed fastening. This approach may be particularlyadvantageous in subjects who have limited dexterity due to their handtremors. Once the electrodes are placed on the wrist or arm, theadhesive electrode holds one end of the hand to the wrist or arm and thepatient can wrap the band around and fasten it. A further advantage tothis deisgn is that the length of the band only needs to be altered atthe end that does not interface with the electrode. As an example, FIG.44A depicts placing the hand palm side up to visualize the electrodesplacement and affix the end of the band. FIG. 44B depicts wrapping theband around the wrist while the band is held in place by the electrodeadhesion. FIG. 44C depicts overlaying the closure mechanism, such asVelcro or a magnetic clasp.

For optimal efficacy and comfort, the device should be aligned on thearm such that it targets the nerves for stimulation and positions thehousing on the dorsal surface of the wrist. There are many ways toaccomplish this through device design. One embodiment depicted in FIG.45A (bottom view) and FIG. 45B (top view) is to use a band 4500 with aslidable electronics housing 4502. The side of the band with theelectrode(s) 4506 is placed and aligned with the ventral side of thewrists using anatomical landmarks with or without other visualindicators. The device can then be wrapped around the hand in one motionand secured with a fastener, in this case a Velcro loop 4508 and a hook3410. The position of the electronics housing 4502 is slideable and hasa connection to the electrodes through the band that is accomplished byan accordian flex circuit or cables 4512 that can slide freely and tuckinto the hand.

For patients with tremor, plugging in small cables like a USB can bedifficult. Therefore, it would be desirable to provide easier interfacesto charge the device. One such way is to use an inductive coil in thedevice. When placed in the proximity of a charging pad, the devicecharges with no cables. This also enables and helps the device to bewaterproof. However, it does have the disadvantage of being slower tocharge and could add to the size of the device. A second possibility isto make a keyed hole 4602, so that patients can easily slide the device4604 into the charger 4600, as shown in FIG. 46. In addition, thepatients then have some structure to brace themselves against. The keyedhole can also be tapered such that the end that device is inserted intois much larger than the device and tapers down to fit the device at theplug. The tapering also helps placement of the device in the basestation.

Another design possibility is a band 4700 with a D-ring 4702 andcinching strap 4704 as shown in FIGS. 47A-47C. Such a device can be laidflat for application of the electrodes 4706 and inductive charging. Thecinching strap allows tightening and positing of the hand with one hand.FIG. 47A shows the band 4700 opened to place the disposable electrodepairs 4706-multiple spaces are provided to customize the spacing fordifferent sizes of wrists. FIG. 47B shows the closure mechanism, andFIG. 47C shows an inductive charger 4708 hooked up to laptop 4710.

Another embodiment shown in FIGS. 48A-48C includes a one ormulti-fingered glove 4800 where one electrode 4802 is a ring around thefinger and a second electrode 4804 is located at the wrist with theelectronics. A major advantage of this design is that it does notrequire any precise positioning due to the nerve location andaccessibility in the fingers. The one fingered glove can be made out offlexible materials, such as a glove.

The terms “about” and “approximately” can mean within 5%, 10%, 15%, or20%, or can mean within 5 degrees or 10 degrees.

It is understood that this disclosure, in many respects, is onlyillustrative of the numerous alternative device embodiments of thepresent invention. Changes may be made in the details, particularly inmatters of shape, size, material and arrangement of various devicecomponents without exceeding the scope of the various embodiments of theinvention. Those skilled in the art will appreciate that the exemplaryembodiments and descriptions thereof are merely illustrative of theinvention as a whole. While several principles of the invention are madeclear in the exemplary embodiments described above, those skilled in theart will appreciate that modifications of the structure, arrangement,proportions, elements, materials and methods of use, may be utilized inthe practice of the invention, and otherwise, which are particularlyadapted to specific environments and operative requirements withoutdeparting from the scope of the invention. In addition, while certainfeatures and elements have been described in connection with particularembodiments, those skilled in the art will appreciate that thosefeatures and elements can be combined with the other embodimentsdisclosed herein.

What is claimed is:
 1. An external system for stimulating at least one nerve in a patient's arm or wrist, the system comprising: a pulse generator; a circumferential band configured to be secured to the patient's arm or wrist, the band supporting a first and a second electrode in electrical communication with the pulse generator, the first and second electrodes being spaced on the band and configured to deliver electrical stimuli from the pulse generator to the patient to preferentially excite a first nerve, the first and second electrodes being arranged and configured such that in a transverse cross-sectional plane of the arm or wrist there is a 90 degree to 180 degree angle between a line connecting the first nerve and the first electrode and a line connecting the first nerve and the second electrode; and a controller configured to signal the pulse generator to deliver the electrical stimuli configured to preferentially stimulate the first nerve via the first and second electrodes to the patient, wherein the system further comprises a switch matrix configured to switch the pulse generator between the first electrode and the second electrode, wherein the first electrode and the second electrode comprise a carbon material.
 2. The system of claim 1, wherein the band supports a third electrode in electrical communication with the pulse generator, the first and third electrodes being spaced on the band so as to deliver electrical stimuli from the pulse generator to the patient to preferentially excite a second nerve selected from the patient's median, radial or ulnar nerve, the first and third electrodes being arranged and configured such that in a transverse cross-sectional plane of the arm or wrist there is a 90 degree to 180 degree angle between a line connecting the second nerve and the first electrode and a line connecting the second nerve and the third electrode, wherein the first nerve and the second nerve are different nerves, wherein the pulse generator is the only pulse generator, wherein the controller is further configured to deliver an alternating stimulation pattern from the pulse generator to the first electrode, second electrode, and third electrode, wherein the stimulation pattern comprises an application of a plurality of bursts of electrical stimulation, wherein each burst comprises a stimulation frequency between 50 Hz and 2,000 Hz, a pulse width between 50 microseconds and 1 millisecond, and a pulse shape selected from the group consisting of monophasic rectangular, biphasic asymmetric rectangular, and biphasic symmetric rectangular.
 3. The system of claim 2, wherein when the circumferential band is secured around the patient's arm or wrist, the first electrode is positioned on a dorsal side of the patient's arm or wrist, the second electrode is positioned on a ventral side of the patient's arm or wrist, and the third electrode is positioned on the patient's arm or wrist in between the first electrode and the second electrode.
 4. The system of claim 2, wherein the controller is configured to deliver an alternating stimulation pattern from the pulse generator to the first electrode, second electrode, and third electrode.
 5. The system of claim 4, wherein the stimulation pattern comprises an application of a plurality of alternating bursts of electrical stimulation delivered in a first pulse train to the first nerve, and a second pulse train delivered to a second, different nerve, wherein the first pulse train and the second pulse train are offset.
 6. The system of claim 2, wherein the controller is further configured to deliver an alternating stimulation pattern from the pulse generator to the first electrode and the second electrode, wherein the stimulation pattern comprises an application of a plurality of bursts of electrical stimulation, wherein each burst comprises a stimulation frequency between 50 Hz and 2,000 Hz, a pulse width between 50 microseconds and 1 millisecond, and a pulse shape selected from the group consisting of monophasic rectangular, biphasic asymmetric rectangular, and biphasic symmetric rectangular.
 7. The system of claim 1, wherein the pulse generator is the only pulse generator.
 8. The system of claim 1, wherein the first and second electrodes comprise a conductive fabric.
 9. The system of claim 1, wherein the first and second electrodes comprise a conductive rubber.
 10. An external system for stimulating at least one nerve in an upper extremity of a patient, the system comprising: a pulse generator; and a band securable to the patient's upper extremity, the band supporting a first and a second electrode in electrical communication with the pulse generator, the first and second electrodes being spaced on the band and configured to deliver electrical stimuli from the pulse generator to the patient to preferentially excite a first nerve, the first and second electrodes being arranged and configured such that in a transverse cross-sectional plane of the upper extremity there is a 90 degree to 180 degree angle between a line connecting the first nerve and the first electrode and a line connecting the first nerve and the second electrode, wherein the system further comprises a controller configured to deliver an alternating stimulation pattern from the pulse generator to the first electrode and the second electrode.
 11. The system of claim 10, further comprising a housing comprising one or more depressible user input buttons, each button located on a side of the housing, and a broad bracing surface on the opposite side of the housing from each button.
 12. The system of claim 10, wherein the first and second electrodes comprise carbon.
 13. The system of claim 10, wherein the first and second electrodes comprise a conductive foam.
 14. The system of claim 10, wherein the first and second electrodes comprise a conductive fabric.
 15. The system of claim 10, further comprising a sensor configured to measure a parameter of the patient.
 16. The system of claim 10, wherein the sensor is configured to detect motion of the patient's upper extremity.
 17. The system of claim 10, wherein the controller is further programmed to adjust one or more parameters of the electrical stimuli based on the parameter of the patient.
 18. The system of claim 10, wherein the band supports a third electrode in electrical communication with the pulse generator, the first and third electrodes being spaced on the band so as to deliver electrical stimuli from the pulse generator to the patient to preferentially excite a second nerve, the first and third electrodes being arranged and configured such that in a transverse cross-sectional plane of the upper extremity there is a 90 degree to 180 degree angle between a line connecting the second nerve and the first electrode and a line connecting the second nerve and the third electrode, wherein the first nerve and the second nerve are different nerves, wherein when the band is secured around the patient's upper extremity, the first electrode is positioned on a dorsal side of the patient's upper extremity, the second electrode is positioned on the ventral side of the patient's upper extremity, and the third electrode is positioned on the patient's upper extremity in between the first electrode and second electrode, wherein the system further comprises a switch matrix configured to switch the pulse generator between the first electrode and the second electrode, wherein the controller is further configured to deliver an alternating stimulation pattern from the pulse generator to the first electrode, second electrode, and third electrode.
 19. A transcutaneous system for stimulating at least one nerve of an upper extremity, the system comprising: a circumferential band configured to be secured to the patient's upper extremity, the band supporting a first and a second electrode in electrical communication with a pulse generator, the first and second electrodes being spaced on the band and configured to deliver electrical stimuli from the pulse generator to the patient to preferentially excite a first nerve, the first and second electrodes being arranged and configured such that in a transverse cross-sectional plane of the upper extremity there is a 90 degree to 180 degree angle between a line connecting the first nerve and the first electrode and a line connecting the first nerve and the second electrode, wherein the band is configured to be in electrical communication with a controller configured to deliver an alternating stimulation pattern from the pulse generator to the first electrode and the second electrode.
 20. The system of claim 19, wherein the band supports a third electrode in electrical communication with a pulse generator, the first and third electrodes being spaced on the band so as to deliver electrical stimuli from the pulse generator to the patient to preferentially excite a second nerve, the first and third electrodes being arranged and configured such that in a transverse cross-sectional plane of the upper extremity there is a 90 degree to 180 degree angle between a line connecting the second nerve and the first electrode and a line connecting the second nerve and the third electrode, wherein the first nerve and the second nerve are different nerves, wherein when the band is secured around the patient's upper extremity, the first electrode is positioned on a dorsal side of the patient's upper extremity, the second electrode is positioned on the ventral side of the patient's upper extremity, and the third electrode is positioned on the patient's upper extremity in between the first electrode and second electrode, and wherein the first electrode, second electrode, and third electrode comprise carbon. 